Abstract
The human motor neuron degenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by loss of function mutations of immunoglobulin mu-binding protein 2 (IGHMBP2), a protein of unknown function that contains DNA/RNA helicase and nucleic acid-binding domains. Reduced IGHMBP2 protein levels in neuromuscular degeneration (nmd) mice, the mouse model of SMARD1, lead to motor neuron degeneration. We report the biochemical characterization of IGHMBP2 and the isolation of a modifier locus that rescues the phenotype and motor neuron degeneration of nmd mice. We find that a 166 kb BAC transgene derived from CAST/EiJ mice and containing tRNA genes and activator of basal transcription 1 (Abt1), a protein-coding gene that is required for ribosome biogenesis, contains the genetic modifier responsible for motor neuron rescue. Our biochemical investigations show that IGHMBP2 associates physically with tRNAs and in particular with tRNA(Tyr), which are present in the modifier and with the ABT1 protein. We find that transcription factor IIIC-220 kDa (TFIIIC220), an essential factor required for tRNA transcription, and the helicases Reptin and Pontin, which function in transcription and in ribosome biogenesis, are also part of IGHMBP2-containing complexes. Our findings strongly suggest that IGHMBP2 is a component of the translational machinery and that these components can be manipulated genetically to suppress motor neuron degeneration.
Highlights
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive neurodegenerative disease [1,2]
We find that transcription factor IIIC-220 kDa (TFIIIC220), an essential factor required for tRNA transcription, and the helicases Reptin and Pontin, which function in transcription and in ribosome biogenesis, are part of IGHMBP2-containing complexes
Our findings strongly suggest that IGHMBP2 is a component of the translational machinery and that these components can be manipulated genetically to suppress motor neuron degeneration
Summary
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive neurodegenerative disease [1,2]. The primary pathology of SMARD1 consists of degeneration of spinal cord motor neurons and axonal loss leading to muscular atrophy [1,2]. SMARD1 results from mutations in the immunoglobulin m-binding protein 2 (IGHMBP2) [1,2]. The human IGHMBP2 is a 993 amino acid protein that contains an RNA/DNA helicase domain (found in the superfamily I helicases), an R3H, single-stranded nucleic acid-binding domain and a zinc finger domain (1 – 3). Proposed functions, based on in vitro data, include transcriptional activation, immunoglobulin class switching and pre-mRNA splicing (4 – 9). The presence of an RNA helicase domain and a single-stranded nucleic acid-binding domain suggests that IGHMBP2 may function in RNA processing, regulation or metabolism
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